Pigmentary diseases are often characterized in the elevated levels of the enzyme tyrosinase in melanocytes; i.e., human and animal cells which synthesize the pigment melanin. There are a variety of pigmentary diseases, such as melasma, melanoma, moles and the like. In particular, moles are susceptible to becoming melanoma after exposure to sunlight which results in increased synthesis of tyrosinase.
Usually commercial forms of depigmenting compositions are based on the use of hydroquinone. However, the hydroquinone preparations are very unstable and cause skin irritation. Hydroquinone compositions can also cause permanent whitening of the skin if used for a prolonged period and at a high concentration. As to treatment of melanoma, this is presently attended to by surgical procedures, since any type of known non-surgical treatment of melanoma is unsatisfactory.
Research work has been conducted in the field of phenolic and diphenolic compounds to serve as a basis for chemotherapeutic treatment of melanoma and skin depigmentation. In particular, 4-S-cysteinylphenol (4-S-CP) and 4-S-cysteaminylphenol (4-S-CAP) have been synthesized and evaluated for cytotoxicity to normal epidermal melanocytes to determine their effectiveness as depigmenting agents and antimelanoma agents. Miura et al, "Synthesis of Cysteinylphenol, Cysteaminylphenol, and Related Compounds, and In Vivo Evaluation of Antimelanoma Effect", Arch. Dermatol Res. (1987) 279:219-225, discloses the effect of 4-S-CAP and 4-S-CP in depigmentation of black hair as manifested by loss of functioning melanocytes. The effectiveness of these compounds was compared against the use of hydroquinone to achieve depigmentation. It was established that 4-S-CAP was a potent agent in prolonging the lifespan of melanoma-bearing mice and hence exhibited inhibition of melanoma growth. The 4-S-CP and the methyl ester of 4-S-CP also exhibited some inhibition of melanoma growth, although not as active as the 4-S-CAP.
The same compounds, 4-S-CP and 4-S-CAP, were also investigated for properties of depigmentation of black guinea pig skin by topical application. The results of this work is reported by Ito et al, "Depigmentation of Black Guinea Pig Skin by Topical Application of Cysteaminylphenol, Cysteinylphenol, and Related Compounds", The Journal of Investigative Dermatology, Vol. 88 No. 1, January 1987. Although the 4-S-CAP demonstrated depigmenting properties, inflammatory changes of the skin of the guinea pigs was prominent. The 4-S-CAP was capable, however, of:
1. decreasing the number of functioning melanocytes; PA1 2. decreasing the amount of epidermal melanin pigments; and PA1 3. degenerating and destroying melanocytes. PA1 a. hypotensive effect; and PA1 b. high toxicity due to the 4-S-CAP being a substrate for monoamineoxidase (MAO) which in the plasma converts 4-S-CAP into an aldehyde form which produces a non-specific cytotoxicity. PA1 i) a biologically effective amount of an active compound selected from the group represented by the formula: ##STR1## wherein R.sub.1 is H or lower alkyl; PA1 with the proviso that when x is 1 one of R.sub.1, R.sub.2 or R.sub.3 is other than H; and PA1 ii) a suitable biologically compatible carrier for the selected active compound. PA1 i) treating human or animal Skin by use of a composition comprising a biologically effective amount of an active compound selected from the group represented by the formula: ##STR2## wherein R.sub.1 is H or lower alkyl; PA1 with the proviso that when x is 1, one of R.sub.1, R.sub.2 or R.sub.3 is other than H and PA1 ii) the selected active compound being used in a suitable biologically compatible carrier. PA1 i) a biologically effective amount of an active compound selected from the group represented by the formula: ##STR3## wherein R.sub.1 is H or lower alkyl; PA1 with the proviso that when x is 1, one of R.sub.1, R.sub.2 or R3 is other than H PA1 ii) the selected active compound being used in a suitable biologically compatible carrier. In one embodiment, this method is useful where the synthesis of melanin is associated with skin pigmentation, melasma and melanoma. PA1 with the proviso that when x is 1, one of R.sub.1, R.sub.2 or R.sub.3 is other than H. PA1 ii) R.sub.1 is CH.sub.3 in formula (III) to yield .alpha.-Me-4-S-CAP in formula (I"); and PA1 iii) R.sub.1 is H in formula (III) to yield N,N-dimethyl-4-S-CAP in formula (I"'). PA1 a biologically effective amount of the active compound selected from the group of formula I is administered in combination with a suitable biologically compatible carrier for the selected active compound. PA1 1. prevent UV radiation activating melanin synthesis in melanocytes; PA1 2. prevent moles from becoming melanoma after exposure to sunlight; and PA1 3. react as a substrate for the enzyme tyrosinase which substrate is an active agent of the compound of formula I in producing toxic components which act as depigmenting agents and possibly as UV blockers in the sunscreen lotion.
4-S-CP and 4-S-CAP were also investigated for their selective cytotoxicity on follicular melanocytes. This was reported by Ito et al, "Selective Cytotoxicity of 4-S-Cysteaminylphenol on Follicular Melanocyte of the Black Mouse: Rational Basis for its Application to Melanoma Chemotherapy", Cancer Research, Jun. 15, 1987 47:3278-3284. It was reported that 4-S-CAP demonstrated cytotoxicity in the depigmentation of black hair follicles, whereas it had no effect on the albino follicles. Hence 4-S-CAP is actively engaged in the melanin synthesis of the melanocytes.
The 4-S-CAP compound, however, has several limitations from the standpoint of practical clinical use. These limitations include: